new 06 terdiman newparadigm - ucsf cme · 2016. 11. 15. · • prolonged flare • active...
TRANSCRIPT
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New Paradigms, New Management: Our Changing Understanding of Ulcerative Colitis and Diverticulitis
Jonathan P. Terdiman, MDProfessor of Clinical Medicine and SurgeryDirector, Gastroenterology Service
Disclosures
• None
2Hospitalized UC Patient|
UC: History• 20 year old woman, college student• Developed bloody diarrhea during midterm
examinations. 10+ BMs per day and night• Roommate brings her to ED
– Pale– Tachycardic (> 120), BP 85/45, afebrile– Abdominal pain, Tender in LLQ, focal rebound– Bloody bowel movements in ED– WBC 16K, Hct 22%, crp 70 mg/L
• Admitted to Hospital
3Hospitalized UC Patient|
In Hospital
• Dehydrated – IV fluids, VS normalize• Diet: Clear liquids
• CT scan
– LB wall thickening and fat stranding, no dilation of the colon• Stools collected for infectious agents
- for culture, E.coli 0157, O&P, C diff
4Hospitalized UC Patient|
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>10 stools/day, continuous bleeding, toxicity, abdominal tenderness/distension, transfusion requirement, colonic dilation on x-ray
<4 stools/day ± blood, normal ESR, no signs of toxicity
>6 bloody stools/day + fever, tachycardia, anemia, or ESR
≥4 stools/day, minimal signs of toxicity
Classification of UC Severity
Kornbluth A, Sachar DB. Am J Gastroenterol. 2010;105:501.
Mild
Moderate
Severe
Fulminant
Predicators of Poor Response or Surgery
6Hospitalized UC Patient|
• Stoolfrequency
• >8or>5after3daysIVrx.
• Percentagebloodystools
• Bodytemperature>37.5
• Heartrate>90bpm
• CRP(>25,>45mg/L)
• Transversecolon>5cm
• Lowhemoglobin<10.5g/dL
• Serumalbumin
• ESR >30mm/h
• Bandemia
• Prolongedflare
• Activeinfection
• Hospitalizationsetting
• Diseaseduration
Lindgren SC et al. Eur J Gastroenterol Hepatol 1998;10(10):831-5. Gonzalez-Lama Y et al. Hepatogastroenterol2008;55(86-87):1609-14. Suzuki Y et al Dig Dis Sci 2006;51(11):2031-8. Cacheux W. et al. A,m J Gastroenterol2008;103(3):637-42. Ananthakrishnan AN et al. A, J Gastroenterol 2008;103(11):2789-98.
Flexible Sigmoidoscopy
7Hospitalized UC Patient|
• Limitedtorectosigmoid• Noprep• Mucosa:
• Edema,Erythema• DiffuseUlceration
• Pattern– Circumferential,continuous,noskipareas
Endoscopic Severity: UC
8Hospitalized UC Patient|
Mild
• Granularmucosa
• Edematous
• Lossofnormalvascularpattern
Sutherland LR, et al. Gastroenterology. 1987;92:1894-1898.
• Coarselygranular
• Smallulcerations
• Friable
Moderate
• Frankulcerations
• Spontaneoushemorrhage
Severe
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Endoscopic Severity Predicts Colectomy
9Hospitalized UC Patient|
Severeendoscopic colitis
Moderateendoscopic colitis
Carbonnel F et al. Dig Dis Sci. 1994;39:1550.
100
0
Colectom
y(%
)
Deep/extensive
ulcers
93%
Mucosaldetachment
30%
Largemucosal
abrasions
26%
Well-likeulcers
17%
>50%→colectomy
100
0Superficial
ulcers
77%
Deep butnonextensive
ulcers
8%
>20%→colectomy
Colectom
y(%
)
Infections in UC
10Hospitalized UC Patient|
• Nobroadspectrumantibiotics• C.difficile
– Oralvanco firstline(40v10%colectomyrate)
– 40%rule:40%ofUCflares,40%nopriorabx,40%colectomyrate
• CMV– IHC+upto20-30%ofsevereUC– Bystanderversuspathogen– Treatboth,avoidCsA
Meanwhile, back in the hospital …
• No progression of exam, VS stable, no need for further transfusion
• PPD placed, Hep serologies sent
• IV steroids started, solumedrol 1 mg/kg (40 mg) daily
11Hospitalized UC Patient|
IV Corticosteroids: Effective in Severe UC
12Hospitalized UC Patient|
Outcomes: Severe UC by Day 15
78% 69% 65% 70%
93%
53%
0%
20%
40%
60%
80%
100%
Dexa100mg x3
HC 400mg M-pred40mg
M-pred0 .75 -1 ..0
mg/kg
HC 400 mg M-pred 64mg
Daily Dose
% R
emis
sion
or
Sub
stan
tial
R
espo
nse
Sood,Aetal.JClinGastroenterol2002;35(4):328-31. Panes,Jetal.Gastroenterology2000;119:903-8.Mantzaris,GJetal.ScandJGastroenterol2001;36:971-4. Mantzaris,GJetal.AmJGastroenterol1994;89:43-6.D’HaensGetal.Gastroenterology2001;120:1323-9. Chapmanetal.Gut1986;27:1210-2
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Hospital Day 3• Patient with minimal response
• Still multiple poorly –formed, bloody bowel movements, cramps (> 10)
• Hgb < 7, 2 units of blood given, CRP > 50, xray with T colon at 4 cm
• Options?1) Wait longer on IV steroids2) Start cyclosporin or tacrolimus3) Start infliximab4) Operation
13Hospitalized UC Patient|
SteroidFailure:Day3assessment
IV Cyclosporin: Highly Effective
15Hospitalized UC Patient|
Outcomes: Severe UC by Day 15
82%69%
79%
56%
91% 86%
64%
0%
20%
40%
60%
80%
100%
4mg/kg 4mg/kg 5mg/kg 4mg/kg 4mg/kg 4mg/kg 4mg/kg
Daily Dose
% R
espo
nse
Lichtiger et al. N Engl J Med 1994;330:1841-5. Stack WA et al. Aliment Pharmacol Ther 1998;12:973-8.Van Gossum A et al. Acta Gastroenterol Belg 1997;60:197-200. Cohen RD et al. Am J Gastroenterol 1999;94:1587-92.Wenzl HH et al. Z Gastroenterol 1998;36:287-93. D’Haens G et al. Gastroenterology 2001;120:1323-9Hyde GM et al. Eur J Gastroenterol Hepatol 1998;10:411-3.
CSA: Colectomy Avoidance with AZA
16Hospitalized UC Patient|
Actis GC et al. BMC Gastro 2007;7:13-19
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17Hospitalized UC Patient|
Jarnerot G, et al. Gastroenterol. 2005;128(7):1805-1811.
80%
70%
60%
40%
10%
0%
29%
67%
Infliximab
Placebo
20%
30%
50%
1.0
0.8
0.6
0.4
0.2
0.0
0 30 60 90
P=0.0038(logrank– test)
TimeinDays
Prob
abilityNotOpe
rated
Infliximab
Placebo
No.ofPatientsatRiskInfliximab 24 17 17 17Placebo 21 7 7 7
Colectomy
Infliximab: IV steroid-refractory UC
18Hospitalized UC Patient|
• 23 GETAID and 6 ECCO centres• 111 pts failing 5 days IV steroids: : Lichtiger score>10• Patients randomized to either i.v.:
• Cys 2mg/kg/d x 1 week, then oral CSA x 91 days• IFX 5mg/kg at weeks 0-2-6
• All patients started on azathioprine 2.5 mg/kg/d• Steroids tapered• Failure:
• No response day 7• Absence Remission Day 98• Relapse Day 7 – 98• Severe AE or Death• Colectomy
CSA vs. IFX: Severe IV Steroid-Refractory UC
CSA vs. IFX: Severe IV Steroid-Refractory UC
19Hospitalized UC Patient|
p=0.97
Response:Lichtiger score< 10anddecrease≥3pointsascomparedtobaseline
85.4% 85.7%
0%
20%
40%
60%
80%
100%
Cys (n=55) IFX(n=56)
Response:Day7
p=0.4960%54%
0%
20%
40%
60%
80%
100%
Cys (n=55) IFX(n=56)
TreatmentFailure*
Laharie etal. 2011
*Failure:• Noresponseday7• AbsenceRemissionDay98• RelapseDay7– 98• SevereAEorDeath• Colectomy
IFX vs CsA (Narula, et al. Am J Gastroenterol 2016; 111:477–491)
Colectomy rates at 12 months
20Hospitalized UC Patient|
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IFX vs CsA (Narula, et al. Am J Gastroenterol 2016; 111:477–491)
• Drug adverse events
21Hospitalized UC Patient| 22Hospitalized UC Patient|
• Nevertogether.Toomuchrisk(20-30%SAE)• SomeExceptions:
1. Cyclosporin:effective,butthenhasallergicreactiontoazathioprine/6-MP.(washoutfor48-72hours)
2. Cyclosporin:intolerableside-effect(washoutfor48-72hours)
3. Infliximab:OncegivenNOCsA
BOTH Cyclosporin and Infliximab?
Infliximab: Not always successful
23Hospitalized UC Patient|
39%30%
26% 30%
0%
10%
20%
30%
40%
50%
UCCS <3 Baron = 0
Week 6 Results
Inflix imabPlacebo
P=0.76
P=0.96
ProbertCSJetal.Gut2003;52:998-1002.• NodifferenceinIBDQ orEuroQol Scores
• RandomizedPlacebo-ControlledTrial• Infliximab5mg/kg@weeks0,2• Placebo
Infliximab failure….Why?
24Hospitalized UC Patient|
Results• IFX:Detectedinallptsstool.• Highestinthefirstdayspost
infusion.• Nonresponders,hadmuch
highamountsofdruglostinstool.
Brandse JF, et al. Presented at DDW; May ,2013. Abstract 157.
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Higher Trough Levels: Better Outcomes
25Hospitalized UC Patient|
Murthy S, et al. 2012
Steroid-free Remission by IFX/ATI Status100
0
60
20
Pat
ient
sin
Rem
issi
on(%
)
80
40
IFX+ATI-
70.0
16.6
28.5
13.0
IFX+ATI+
IFX-ATI-
IFX-ATI+
P=0.84
P=0.073P<0.001
Serum IFX≤ 2µg/ml
Serum IFX> 2µg/ml
Steroid-free Remission by IFX Trough Status100
0
60
20P
atie
nts
inR
emis
sion
(%)
80
4017.5
69.4
P<0.001
Colectomy by IFX Trough Status100
0
60
20Col
ecto
my
(%)
80
40
Serum IFX≤ 2µg/ml
55.5
17.7
Serum IFX> 2µg/ml
P<0.001
• 125Steroid-RefractoryUCpts• IFX“Infliximab”;ATI“Antibodyto
Infliximab”• TroughInfliximab>2µg/ml
• Remission:OR10(3,35)• Colectomy:0.18(0.07,0.44)
Accelerated Infliximab Dosing: Success ?
26Hospitalized UC Patient|
6.7%
40%
0% 20% 40% 60% 80%
100%
ColectomyDuringInduction
Accelerated Normal
• Retrospective• 50hospitalizedUCpts• Corticosteroidrefractory• Standarddoseinfliximab:5mg/kgWeeks0,2,6,
thenq8w• Accelerateddose:3doseswithinmedian24days
Gibson DJ et al. Clin Gastroenterol Hepatol 2014
Colectomy for severe UC• Colectomy
– Surgical consult by day 3 for refractory patients– Toxic megacolon, perforation, refractory
bleeding– Failure of medical therapy at 7-10 days
• Total abdominal colectomy with Hartmann– Mortality < 1%– Laparoscopic or robotic– J pouch in 3 stages if eligible, but NOT during
acute illness
27Hospitalized UC Patient|
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ColonicDiverticulitis:History
• 57yearoldmanwithsuddenonsetofLLQpain,constipationandfever
• Tis38.2,LLQtendertopalpationwithpalpablemass,butnorebound
• WBCis16K• CT
Diverticulitis• IVabx• IRplacesdrainagecatheter,Cx +E.coli• Within48hourspainandfeverandelevatedWBCresolve
• Management?1. Sigmoidcolectomypriortodischarge2. Sigmoidcolectomyafter2-4weeksofabx and
drainage3. Abx for2weeks,drainremovalafterabscess
resolves,observation
Departmentof Medicine
Burden of Disease• Prevalence of diverticulosis increased with age, affected 70%
of individuals 80+ years old• It is the most common finding reported on
colonoscopy
3
Everhart et al, Gastroenterology 2009
Taxonomy
Symptomaticuncomplicateddiverticular disease(SUDD)
Segmentalcolitisassociatedwithdiverticulosis (SCAD)
Strate et al, Am J Gastroenterol 2012
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Departmentof Medicine
Riskof diverticulitis
• The cumulative diverticulitis probability over 130 months was4.3 % . For every additional decade of life, there was a 24 % lower risk of diverticulitis.
Strate et al, Am J Gastroenterol 2012
Departmentof Medicine
vAge• Decreased risk with increased age of dx
vMedications• NSAIDs, steroids, opiates increase risk for
diverticulitis• Calcium channel blockers, statins may be protective
vGenetics• Twin studies Sweden and Denmark
• OR 3x higher in monozygotic vs. dizygotic twins• 40-50% of liability attributable to genetic factors
Templeton and Strate Curr Gastroenterol 2012
Riskfactors fordiverticulitis
Departmentof Medicine
Fiber Helps!• British study of cohort of 700,000
women with no known diverticulardisease, 6- year follow-up.
• 17,000 admitted to hospital withdiverticular disease.
• Higher intake of dietary fiber isassociated with reduced risk ofdiverticular disease.
29Crowe et al, Gut 2014
• The Health Professionals Follow-up Study,cohort ofmen prospectively followed 1986-2004.
• 47,000 men, age 40-75 years, baseline were free ofdiverticulosis and returned a food-frequency questionnaire.
• Outcome was incident diverticulitis and diverticularbleeding.
Nuts, corn, popcorn to blame?
Strate et al, JAMA 2008
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Departmentof Medicine
No increased risk!
Strate et al, JAMA 2008
Antibiotics for acute diverticulitis?• MulticenterrandomizedcontrolledtrialinSwedenandIcelandof623patientswithuncomplicatedleft-sideddiverticulitis(confirmedonCT),excludedifabscess,fistula,freeair,highfever,peritonitis,orsepsis
• Randomizedtobroad-spectrumantibioticsofIVfluidsalone
• Alsonodifferenceinmeanhospitalstay,complications,orrecurrentdiverticulitisnecessitatingre-admissionover1year
• Authorsconcludedthatantibioticsshouldbeusedonlyincasesofcomplicateddiverticulitis
Chabok et al, Br J Surg 2012
Antibiotics for acute diverticulitis?
• Retrospectivecohortof246patientsadmittedwithdiverticulitisin2011toVastmanlandHospital,Sweden
• AllcasesconfirmedbyCT,195withAUD• 178(91.3%)werenotgivenantibiotics• 6ptsreadmitted,2hadabscess• Only25patients(12.8%)presentedwithrecurrenceat1year
Wille-Jorgensen Coch Syst Rev 2012
When to operate?
• Emergency• Free Perforation• Diffuse Peritonitis• Complete Colonic Obstruction
• Relative emergency• Fail medical therapy, 72-96 hours• Recurrence in the same admission• Partial colonic obstruction• Immunocompromised patients• Unable to r/o carcinoma
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Whathappensafteranepisodeofdiverticulitis?
Recurrence free survival N=2366
3165patients12KaiserhospitalsinSouthernCaliforniaEmergentcolectomy 20%Nonopmanagement80%Ofthose
13%hadrecurrence7%hadcolectomy
Meanfollowup9years
0.00
0.25
0.50
0.75
1.00
Time to Recurrence (months)
0 20 40 60 80 100
0.00
0.25
0.50
0.75
1.00
Time to Recurrence (months)
0 20 40 60 80 100
Freefromrecurrence Freefromrecurrencewcomplication
Hazard Ratio 95% CI
Retroperitoneal Abscess
4.5 1.1-18.4
Family history of diverticulitis
2.2 1.4-3.2
Segment > 5 cm 1.7 1.3-2.3Right colonic disease
0.27 0.09-0.86
RiskofRecurrenceper#ofpriorepisodes
Number Patients Follow-Up Recurrence0 2052 9years 5%1 222 9years 11%2 65 10years 21%3 18 9years 33%4 5 7years 57%
Do Multiple Recurrences Predict a Less Favorable Outcome?
• Prior episodes 1-2 >2• # of patients 122 35• Perforation 17% 0%• Stoma 37% 3%
Chapman et al, Ann Surg 2006
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Surgeryafterpercutaneousdrainage
LambandKaiserDis ColonRect 2104 LiD,etal.AnnSurgery2014
Departmentof Medicine
• Retrospective chart review of 1100 cases diverticulitis atUCLA Veteran’s Administration Hospital + matched controls
• Cases were 4.7 fold (CI 1.6-14; p = 0.006) more likely to bediagnosed with IBS (CI 1.6-14)
• 2.4 fold (CI 1.6-3.6; p = < 0.001) more likely to be diagnosedwith a functional bowel disorder
Post-diverticulitis IBS
Incidence of new IBS diagnosis
Cohen et al, Clin Gastroenterol Hepatol 2013
Incidence of new functional bowel disorder
Departmentof Medicine
IBS and diverticulosis
23
Jung et al, Am J Gastroenterol 2010
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• Case series demonstrate chronic inflammation inbiopsy specimens taken from within and around diverticula of patients without overt diverticulitis orcolitis.
– Abnormal pathology in random biopsies taken from 16 of 17 patients with diverticulosis, with most demonstrating alymphocytic infiltrate without overt colitis
– There was evidence of chronic inflammation in and arounddiverticula in three quarters of resected specimens from 930patients undergoing surgery for symptomatic uncomplicateddiverticular disease but not overt diverticulitis
Floch et al, J C lin Gastroenterol 2006; Horgan et al, D is Colon Rectum 2001
InflammationDepartmentof Medicine
Visceral hypersensitivity
• Study of 10 patients with asymptomatic diverticulosis (ADD),11SUDD patients, 9 controls.
• In the rectum, the SUDD group had increased perception scores compared with the control group (p = 0.010) and the ADD group (p = 0.030). In the sigmoid colon, in the pre- and postprandial periods, the SUDD group had increased perception scores compared with the control group (p = 0.018)
21Clemens et al, Gut 2004
Departmentof Medicine
Colonic Motility
• 12 patients with SUDD underwent 24-hour colonic manometric recordings and compared to 20 healthy controls
• Patients with SUDD displayed increased duration of rhythmic, low frequency, contractile activity, particularly inthe segments bearing diverticular – a pattern described as“spastic colon”.
• Patients with diverticulosis have significantly reduceddensity of interstitial cells of Cajal – the so- called“pacemaker cells” of the intestine.
25Bassotti et a l, D ig Dis 2012; Bassotti Eur J Gastroenterol Hepatol 2004
• Hypothesis - Shifts in intestinal microbiota lead tochronic inflammation. Fecal stasis may lead tochronic dysbiosis in turn promote formation ofabnormal metabolites.
• Study of 90 patients with history of diverticulitis, 60%had small bowel bacterial overgrowth
• Use of probiotics and rifaximin help symptoms?
Intestinal Microbiota?
27Tursi et al, W orld J Gastroenterol 2005
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Departmentof Medicine
New Paradigm ofchronicillness?
Strate et al, Am J Gastroenterol 2012
Departmentof Medicine
• Multicenter, double-blind, placebo-controlled trial of 120 patients in Germany• Randomized to mesalazine 1g PO TID vs. placebo
• 6 week trial, primary end point = change in abdominal pain after 4 weeks• A daily dose of 3.0 g mesalazine may relieve pain of uncomplicated
diverticular disease.
MesalamineDifference of daily pain intensity score
Median
time to
complete
painrelief
%patients
with com
pletepain
relief
K ru is et al, A ilment Pharmacol Ther 2013
Departmentof Medicine
Mesalamine
• Multicenter, double-blinded, placebo-controlled study. 210 SUDD patients randomized to mesalazine (1.6g/day) + probiotic placebo, probiotic + mesalazine placebo, probiotic + mesalazine, placebo only) for 10 days/ mo x 12 months
• Both cyclic mesalazine and Lactobacillus casei subsp., particularly when given in combination, appear to be better than placebo for maintaining remission of symptomatic uncomplicated diverticular disease
placebo
Tursi et al, A l Pharm Ther, 2013
Mesalazine + lactobacillus
lactobacillusmesalazine
Departmentof Medicine
Rifaximin for SUDD
• In symptomatic uncomplicated diverticular disease, treatment with rifaximin plus fibre supplementation is effective in obtaining symptom relief and preventing complications at 1 year
• NNT = 3 for symptom relief; NNT = 59 for complicationsBianchi et al, Aliment Pharmacol Ther 2011
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Departmentof Medicine
CombinationRxforSUDD
• 218 patients with recurrentdiverticulitis
• Randomized to rifaximin 400mg po bid + mesalazine 2.4g/day x 7 days each month vs. rifaximin alone
• Severity of symptoms improved significantly in dual therapy group and more likely to prevent recurrence
Tursi et al, D ig Liver D is 2002Gastroenterology 2014 147, 793-802DOI: (10.1053/j.gastro.2014.07.004)
Mesalamine Did Not Prevent Recurrent Acute Diverticulitis in Phase 3 Controlled Trials
(N = 590, 592)
Raskin JPGastroenterology2014
Departmentof Medicine
Rifaximin forAcute RecurrentDiverticulitis
• Multicenter, randomized, open controlled study in 165patients with recent episode of diverticulitis
• Rifaximin 400mg BID + fiber vs. fiber alone for 1 week/ month x 12 months
• OR 3.2 (95% CI 1.16-8.82, p=0.025)• Cyclic rifaximin treatment reduces the risk of recurrences
of diverticulitis.
Lanas et al, D ig Liver D is 2013
TakeHomePoints
• IVabx maynotbeneededforacuteuncomplicateddiverticulitis.
• Operativetherapyisrarelyneededforrecurrentuncomplicateddiverticulitisorcomplicateddiverticulitis.
• Diverticulardiseaseiscomplexdisorder(motility,heightenedvisceralsensation,bacterialovergrowth,immune)andnoveltherapiesmaybeeffective.